Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity

ABSTRACT

The present invention is a method for the treatment of obesity, for promoting weight loss and/or suppressing appetite comprising administering to a subject in need thereof a therapeutically effective amount of one or more novel benzo-fused heterocycle sulfamide derivatives of formula (I) as herein defined.

This application claims the benefit of U.S. Provisional Application60/751,499, filed on Dec. 19, 2005, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to the use of benzo-fused heterocyclesulfamide derivatives for the treatment of obesity, for promoting weightloss and/or for suppressing appetite.

BACKGROUND OF THE INVENTION

Obesity is a state of excess adipose tissue mass. Although often viewedas equivalent to increased body weight, this need not be the case-leanbut very muscular individuals may be overweight by arbitrary standardswithout having increased adiposity. Body weights are distributedcontinuously in populations, so that a medically meaningful distinctionbetween lean and obese is somewhat arbitrary. Obesity is therefore moreeffectively defined by assessing its linkage to morbidity or mortality.

Although not a direct measure of adiposity, the most widely used methodto gauge obesity is the body mass index (BMI), which is equal toweight/height² (in kg/m²). Other approaches to quantifying obesityinclude anthropometry (skin-fold thickness), densitometry (underwaterweighing), computed tomography (CT) or magnetic resonance imaging (MRI),and electrical impedance. Using data from the Metropolitan Life Tables,BMIs for the midpoint of all heights and frames among both men and womenrange from 19 to 26 kg/m²; at a similar BMI, women have more body fatthan men. Based on unequivocal data of substantial morbidity, a BMI of30 is most commonly used as a threshold for obesity in both men andwomen. Large-scale epidemiologic studies suggest that all-cause,metabolic, and cardiovascular morbidity begin to rise (albeit at a slowrate) when BMIs are ≧25, suggesting that the cut-off for obesity shouldbe lowered. Some authorities use the term overweight (rather than obese)to describe individuals with BMIs between 25 or 27 and 30. A BMI between25 and 30 should be viewed as medically significant and worthy oftherapeutic intervention, especially in the presence of risk factorsthat are influenced by adiposity, such as hypertension and glucoseintolerance.

Recent data from the National Health and Nutrition Examination Surveys(NHANES) show that the percent of the American adult population withobesity (BMI>30) has increased from 14.5% (between 1976 and 1980) to22.5% (between 1998 and 1994). As many as 50% of U.S. adults ≧20 yearsof age were overweight (defined as BMI>25) between the years of 1998 and1991. Because substantial health risks exist in many individuals withBMI between 25 and 30, the increasing prevalence of medicallysignificant obesity raises great concern. Obesity is more common amongwomen and in the poor; the prevalence in children is also rising at aworrisome rate.

Obesity has major adverse effects on health. Morbidly obese individuals(>200% ideal body weight) have as much as a twelve-fold increase inmortality. Morality rates rise as obesity increases, particularly whenobesity is associated with increased intraabdominal fat (see above). Itis also apparent that the degree to which obesity affects particularorgan systems is influenced by susceptibility genes that vary in thepopulation. Obese individuals have a 50-100% increased risk of prematuredeath from all causes compared to individuals with normal body weight.Over 300,000 deaths a year in the United States may be attributable toobesity.

There remains a need to provide an effective treatment for obesity.

SUMMARY OF THE INVENTION

The present invention is directed to a method for the treatment ofobesity, for promoting weight loss and/or for suppressing appetitecomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula (I)

wherein

R¹ and R² are each independently selected from the group consisting ofhydrogen and lower alkyl;

R⁴ is selected from the group consisting of hydrogen and lower alkyl;

a is an integer from 1 to 2;

is selected from the group consisting of

wherein b is an integer from 0 to 4; and wherein c is an integer from 0to 2;

each R⁵ is independently selected from the group consisting of halogen,lower alkyl and nitro;

provided that when

then a is 1;

or a pharmaceutically acceptable salt thereof.

The present invention is further directed to a method for the treatmentof obesity, for weight loss and/or for suppressing appetite comprisingadministering to a subject in need thereof a therapeutically effectiveamount of compound of formula (II)

or a pharmaceutically acceptable salt thereof.

The present invention is further directed to a method for treatingobesity, promoting weight loss and/or suppressing appetite comprisingco-therapy with a therapeutically effective amount of at least oneweight loss promoting agent and/or at least one appetite suppressingagent and a compound of formula (I) or formula (II) as described herein.In an embodiment, the present invention is directed to a method fortreating obesity and/or promoting weight loss comprising co-therapy withat least one weight loss promoting agent and a compound of formula (I)as described here, preferably Compound #8 as described herein.

Exemplifying the invention is a method of treating obesity comprisingadministering to a subject in need thereof a therapeutically effectiveamount of any of the compounds described above. In another example, theinvention is directed to a method of promoting weight loss comprisingadministering to a subject in need thereof a therapeutically effectiveamount of any of the compounds described above. In another example, theinvention is directed to a method of suppressing appetite comprisingadministering to a subject in need thereof a therapeutically effectiveamount of any of the compounds described above. Further exemplifying theinvention is a method for delaying gastic emptying comprisingadministering to a subject in need thereof a therapeutically effectiveamount of any of the compound described herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a method for the treatment ofobesity, for promoting weight loss and/for suppressing appetitecomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R¹, R² and R⁴ are as herein defined. The present invention is furtherdirected to a method for delaying gastic emptying comprisingadministering to a subject in need thereof a therapeutically effectiveamount of any of the compounds described herein.

The present invention is further directed to the treatment of obesitycomprising administering to a subject in need thereof, co-therapy with atherapeutically effective amount of at least one weight loss promotingagent and/or at least one appetite suppressing agent and a compound offormula (I) or formula (II) as described herein.

In one embodiment of the present invention the present invention isdirected to a methods for the treatment of obesity comprisingadministering to a subject in need thereof a therapeutically effectiveamount compounds of formula (I) or (II) as previously described or theirpharmaceutical salts wherein the weight lost is fat and in a morepreferred embodiment is white adipose tissue.

In one embodiment of the present invention the present invention isdirected to a methods for promoting weight loss comprising administeringto a subject in need of or desiring to loss weight a therapeuticallyeffective amount compounds of formula (I) or (II) as previouslydescribed or their pharmaceutical salts wherein the weight lost is fatand in a more preferred embodiment is white adipose tissue.

As used herein, the term “obesity” shall be defined as a body mass index(BMI) of greater than or equal to about 25, preferably a BMI of greaterthan or equal to about 30. Thus as used herein, the term “obesity” shallinclude both overweight and clinically obese subjects/patients.

As used herein, the term “weight loss promoting agent” shall mean anypharmaceutical agent which promotes weight loss. Suitable examplesinclude, but are not limited to rimonabant, orlistat, sibutramine,mazindol, benzphetamine, phenmetrazine, phentermine, diethylpropion,mazindol, phenylpropanolamine, ephedrine, quipazine, fluoxetine,sertraline, fenfluramine, dexfenfluramine, apomorphine, Exendin,dehydroepiandrosterone, etiocholandione, testosterone, oxandrolone,topiramate, and the like. Preferably, the weight loss promoting agent isrimonabant, topiramate, orlistat or sibutramine. Similarly, as usedherein, the term “appetite suppressing agent” shall mean anypharmaceutical agent or natural product which suppresses appetite whichinclude, but are not limited to, appetite-suppressants acting throughadrenergic mechanisms such as benzphetamine, phenmetrazine, phentermine,diethylpropion, mazindol, sibutramine, phenylpropanolamine or,ephedrine; appetite-suppressant agents acting through serotonergicmechanisms such as quipazine, fluoxetine, sertraline, fenfluramine, ordexfenfluramine; appetite-suppressant agents acting through dopaminemechanisms, eg, apomorphine; appetite-suppressant agents acting throughhistaminergic mechanisms (eg, histamine mimetics, H3 receptormodulators); enhancers of energy expenditure such as beta-3 adrenergicagonists and stimulators of uncoupling protein function; leptin andleptin mimetics; neuropeptide γ antagonists; melanocortin-1, 3 and 4receptor modulators; cholecystokinin agonists; glucagon-like peptide-1(GLP-1) mimetics and analogues (eg, Exendin); androgens (eg,dehydroepiandrosterone and derivatives such as etiocholandione),testosterone, anabolic steroids (eg, oxandrolone), and steroidalhormones; galanin receptor antagonists; cytokine agents such as ciliaryneurotrophic factor; amylase inhibitors; enterostatin agonists/mimetics;orexin/hypocretin antagonists; urocortin antagonists; bombesin agonists;modulators of protein kinase A; corticotropin-releasing factor mimetics;cocaine- and amphetamine-regulated transcript mimetics; calcitonin-generelated peptide mimetics; and fatty acid synthase inhibitors.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

Wherein the present invention is directed to co-therapy or combinationtherapy, comprising administration of one or more compound(s) of formula(I) or formula (II) and one or more weight loss promoting agent and/orat least one appetite suppressing agent, “therapeutically effectiveamount” shall mean that amount of the combination of agents takentogether so that the combined effect elicits the desired biological ormedicinal response. For example, the therapeutically effective amount ofco-therapy comprising administration of a compound of formula (I) orformula (II) and at least one weight loss promoting agent and/or atleast one appetite suppressing agent would be the amount of the compoundof formula (I) or formula (II) and the amount of the weight losspromoting agent and/or at least one appetite suppressing agent that whentaken together or sequentially have a combined effect that istherapeutically effective. Further, it will be recognized by one skilledin the art that in the case of co-therapy with a therapeuticallyeffective amount, as in the example above, the amount of the compound offormula (I) or formula (II) and/or the amount of the weight losspromoting agent and/or at least one appetite suppressing agentindividually may or may not be therapeutically effective.

As used herein, the terms “co-therapy” and “combination therapy” shallmean treatment of a subject in need thereof by administering one or morecompounds of formula (I) or formula (II) in combination with one or moreweight loss promoting agent and/or the appetite suppressing agent,wherein the compound(s) of formula (I) or formula (II) and the weightloss promoting agent and/or the appetite suppressing agent areadministered by any suitable means, simultaneously, sequentially,separately or in a single pharmaceutical formulation. Where thecompound(s) of formula (I) or formula (II) and the weight loss promotingagent and/or the appetite suppressing agent are administered in separatedosage forms, the number of dosages administered per day for eachcompound may be the same or different. The compound(s) of formula (I) orformula (II) and the weight loss promoting agent” and/or the appetitesuppressing agent may be administered via the same or different routesof administration. Examples of suitable methods of administrationinclude, but are not limited to, oral, intravenous (iv), intramuscular(im), subcutaneous (sc), transdermal, and rectal. Compounds may also beadministered directly to the nervous system including, but not limitedto, intracerebral, intraventricular, intracerebroventricular,intrathecal, intracisternal, intraspinal and/or peri-spinal routes ofadministration by delivery via intracranial or intravertebral needlesand/or catheters with or without pump devices. The compound(s) offormula (I) or formula (II) and the weight loss promoting agent and/orthe appetite suppressing agent (s) may be administered according tosimultaneous or alternating regimens, at the same or different timesduring the course of the therapy, concurrently in divided or singleforms.

In an embodiment of the present invention R¹ is selected from the groupconsisting of hydrogen and methyl. In another embodiment of the presentinvention R² is selected from the group consisting of hydrogen andmethyl. In yet another embodiment of the present invention R¹ and R² areeach hydrogen or R¹ and R² are each methyl.

In an embodiment of the present invention —(CH₂)_(a)— is selected fromthe group consisting of —CH₂— and —CH₂—CH₂—. In another embodiment ofthe present invention —(CH₂)_(a)— is —CH₂—.

In an embodiment of the present R⁴ is selected from the group consistingof hydrogen and methyl, preferably, R⁴ is hydrogen.

In an embodiment of the present invention a is 1.

In an embodiment of the present invention b is an integer from 0 to 2.In another embodiment of the present invention c is an integer from 0 to2. In another embodiment of the present invention b is an integer from 0to 1. In another embodiment of the present invention c is an integerfrom 0 to 1. In yet another embodiment of the present invention the sumof b and c is an integer form 0 to 2, preferably an integer form 0 to 1.In yet another embodiment of the present invention b is an integer from0 to 2 and c is 0.

In an embodiment of the present invention,

is selected from the group consisting of

In another embodiment of the present invention,

is selected from the group consisting of

In an embodiment of the present invention,

is selected from the group consisting of2-(2,3-dihydro-benzo[1,4]dioxinyl), 2-(benzo[1,3]dioxolyl),3-(3,4-dihydro-benzo[1,4]dioxepinyl),2-(6-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(6-fluoro-2,3-dihydro-benzo[1,4]dioxinyl), 2-(chromanyl),2-(5-fluoro-2,3-dihydro-benzo[1,4]dioxinyl),2-(7-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(6-chloro-benzo[1,3]dioxolyl),2-(7-nitro-2,3-dihydro-benzo[1,4]dioxinyl),2-(7-methyl-2,3-dihydro-benzo[1,4]dioxinyl),2-(5-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(6-bromo-2,3-dihydro-benzo[1,4]dioxinyl),2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(8-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(2,3-dihydro-naphtho[2,3-b][1,4]dioxinyl) and2-(4-methyl-benzo[1,3]dioxolyl).

In another embodiment of the present invention,

is selected from the group consisting 2-(benzo[1,3]dioxolyl),2-(2,3-dihydro-benzo[1,4]dioxinyl),2-(6-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(7-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(7-methyl-2,3-dihydro-benzo[1,4]dioxinyl),2-(6-bromo-2,3-dihydro-benzo[1,4]dioxinyl) and2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxinyl). In another embodimentof the present invention

is selected from the group consisting of2-(2,3-dihydro-benzo[1,4]dioxinyl),2-(7-methyl-2,3-dihydro-benzo[1,4]dioxinyl) and2-(6-bromo-2,3-dihydro-benzo[1,4]dioxinyl).

In an embodiment of the present invention R⁵ is selected from the groupconsisting of halogen and lower alkyl. In another embodiment of thepresent invention R⁵ is selected from chloro, fluoro, bromo and methyl.

In an embodiment of the present invention, the stereo-center on thecompound of formula (I) is in the S-configuration. In another embodimentof the present invention, the stereo-center on the compound of formula(I) is in the R-configuration.

In an embodiment of the present invention the compound of formula (I) ispresent as an enantiomerically enriched mixture, wherein the %enantiomeric enrichment (% ee) is greater than about 75%, preferablygreater than about 90%, more preferably greater than about 95%, mostpreferably greater than about 98%.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. R¹, R³, R⁴, X—Y and A) are independently selected to be anyindividual substituent or any subset of substituents selected from thecomplete list as defined herein.

Representative compounds of the present invention, are as listed inTables 1 below. Additional compounds of the present invention are aslisted in Table 3. In Tables 1 and 2 below, the column headed “stereo”defines the stereo-configuration at the carbon atom of the heterocycleattached at the starred bond. Where no designation is listed, thecompound was prepared as a mixture of stereo-configurations. Where an“R” or “S” designation is listed, the stereo-configuration was based onthe enantiomerically enriched starting material. TABLE 1 RepresentativeCompounds of Formula (I)

ID No.  

Ste- reo  (CH₂)_(a)  NR⁴  R¹  R²  1 2-(2,3-dihydro- CH₂ NH H Hbenzo[1,4]dioxinyl)  2 2-(benzo[1,3]dioxolyl) CH₂ NH H H  33-(3,4-dihydro-2H- CH₂ NH H H benzo[1,4]dioxepinyl)  4 2-(2,3-dihydro- SCH₂ NH H H benzo[1,4]dioxinyl)  5 2-(2,3-dihydro- R CH₂ NH H Hbenzo[1,4]dioxinyl)  6 2-(2,3-dihydro- CH₂ NH meth- meth-benzo[1,4]dioxinyl) yl yl  7 2-(2,3-dihydro- CH₂ N(CH₃) H Hbenzo[1,4]dioxinyl)  8 2-(6-chloro-2,3-di- S CH₂ NH H H hydrobenzo[1,4]dioxinyl)  9 2-(6-fluoro-2,3-di- S CH₂ NH H H hydrobenzo[1,4] dioxinyl)10  2-(chromanyl) CH₂ NH H H 13 2-(5-fluoro-2,3-di- S CH₂ NH H Hhydrobenzo[1,4] dioxinyl) 14 2-(7-chloro-2,3-di- S CH₂ NH H Hhydrobenzo[1,4] dioxinyl) 15 2-(6-chloro- CH₂ NH H H benzo[1,3]dioxolyl)16 2-(2,3-dihydro- CH₂CH₂ NH H H benzo[1,4]dioxinyl) 182-(7-nitro-2,3-dihydro- S CH₂ NH H H benzo[1,4]dioxinyl) 192-(7-methyl-2,3-di- S CH₂ NH H H hydrobenzo[1,4] dioxinyl) 202-(5-chloro-2,3-di- S CH₂ NH H H hydrobenzo[1,4] dioxinyl) 222-(8-methoxy-2,3- S CH₂ NH H H dihydrobenzo[1,4] dioxinyl) 242-(6-bromo-2,3-di- S CH₂ NH H H hydrobenzo[1,4] dioxinyl) 292-(6,7-dichloro-2,3- S CH₂ NH H H dihydrobenzo[1,4] dioxinyl) 302-(8-chloro-2,3-di- S CH₂ NH H H hydrobenzo[1,4] dioxinyl) 332-(2,3-dihydro- S CH₂ NH H H naphtho[2,3-b][1,4] dioxinyl) 352-(4-methyl- CH₂ NH H H benzo[1,3]dioxolyl)

TABLE 2 Additional Compounds of the Present Invention

ID No.

Stereo X NR¹⁴ R¹¹ R¹² 23 2-(5-methoxy-2,3-di- S CH₂ NH H Hhydrobenzo[1,4]dioxinyl) 26 2-(6-methylcarbonyl-2,3- S CH₂ NH H Hdihydrobenzo[1,4] dioxinyl) 32 2-(6-methoxycarbonyl- S CH₂ NH H H2,3-dihydrobenzo[1,4] dioxinyl) 34 2-(6-hydroxymethyl-2,3- S CH₂ NH H Hdihydrobenzo[1,4] dioxinyl) 36 2-(7-amino-2,3-dihydro- S CH₂ NH H Hbenzo[1,4]dioxinyl)

As used herein, unless otherwise noted, “halogen” shall mean chlorine,bromine, fluorine and iodine.

As used herein, unless otherwise noted, the term “alkyl” whether usedalone or as part of a substituent group, includes straight and branchedchains. For example, alkyl radicals include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.Unless otherwise noted, “lower” when used with alkyl means a carbonchain composition of 1-4 carbon atoms.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., alkyl, aryl, etc.), thatgroup may have one or more substituents, preferably from one to fivesubstituents, more preferably from one to three substituents, mostpreferably from one to two substituents, independently selected from thelist of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl-alkyl-amino-carbonyl-alkyl” substituentrefers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows DCC = Dicyclohexyl Carbodiimide DCE =Dichloroethane DCM = Dichloromethane DIPEA or DIEA =Diisopropylethylamine DMF = N,N-Dimethylformamide DMSO =Dimethylsulfoxide EDC = Ethylcarbodiimide Et₃N or TEA = TriethylamineEt₂O = Diethyl ether EA or EtOAc = Ethyl acetate EtOH = Ethanol IPA =2-propanol Hept = Heptane HOBT = 1-Hydroxybenzotriazole HPLC = HighPressure Liquid Chromatography LAH = Lithium Aluminum Hydride M or MeOH= Methanol NMR = Nuclear Magnetic Resonance Pd—C = Palladium on CarbonCatalyst RP HPLC = Reverse Phase High Pressure Liquid Chromatography RTor rt = Room temperature TEA Triethylamine TFA = Trifluoroacetic AcidTHF = Tetrahydrofuran TLC = Thin Layer Chromatography

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichloroactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

Compounds of formula (I) may be prepared according to the processoutlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is reacted withsulfamide, a known compound, preferably wherein the sulfamide is presentin an amount in the range of about 2 to about 5 equivalents, in anorganic solvent such as THF, dioxane, and the like, preferably at anelevated temperature in the range of about 50° C. to about 100° C., morepreferably at about reflux temperature, to yield the correspondingcompound of formula (Ia).

Alternatively, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XI), a known compound orcompound prepared by known methods, in the presence of a base such asTEA, DIPEA, pyridine, and the like, in an organic solvent such as DMF,DMSO, and the like, to yield the corresponding compound of formula (I).

Compounds of formula (X) wherein

may be prepared according to the process outlined in Scheme 2.

Accordingly, a suitably substituted compound of formula (XII), a knowncompound or compound prepared by known method (for example as describedin Scheme 3 above) is reacted with NH₄OH, a known compound, optionallyin an organic solvent such as acetonitrile, and the like, to yield thecorresponding compound of formula (XIII).

The compound of formula (XIII) is reacted with a suitably selectedreducing agent, such as LAH, and the like, and the like, in an organicsolvent such as THF, diethyl ether, and the like, to yield thecorresponding compound of formula (Xa).

Compounds of formula (X) wherein

is selected from

may be prepared according to the process outlined in Scheme 3.

Accordingly, a suitably substituted compound of formula (XIV), a knowncompound or compound prepared by known methods, is reacted with NH₄OH,in the presence of a coupling agent such as DCC, and the like,optionally in an organic solvent such as acetonitrile, and the like, toyield the corresponding compound of formula (XV).

The compound of formula (XV) is reacted with a suitably selectedreducing agent, such as LAH, and the like, in an organic solvent such asTHF, diethyl ether, and the like, to yield the corresponding compound offormula (Xb).

Compounds of formula (X) wherein

is selected from

and wherein a is 2, may be prepared according to the process outlined inScheme 4.

Accordingly, a suitably substituted compound of formula (XVI) wherein J¹is a suitable leaving group such as Br, Cl, I, tosyl, mesyl, triflyl,and the like, a known compound or compound prepared by known methods(for example, by activating the corresponding compound wherein J¹ isOH), is reacted with a cyanide such as potassium cyanide, sodiumcyanide, and the like, in an organic solvent such as DMSO, DMF, THF, andthe like, to yield the corresponding compound of formula (XVII).

The compound of formula (XVII) is reduced according to known methods,for example by reacting with a suitable reducing agent such as LAH,borane, and the like, to yield the corresponding compound of formula(Xc).

Compounds of formula (X) wherein

is selected from

and wherein a is 1, may be prepared according to the process outlined inScheme 5.

Accordingly, a suitably substituted compound of formula (XVIII), a knowncompound or compound prepared by known methods is activated, accordingto known method, to yield the corresponding compound of formula (XIX),wherein J² is a suitable leaving group, such tosylate, Cl, Br, I,mesylate, triflate, and the like.

The compound of formula (XIX) is reacted with a phthalimide salt such aspotassium phthlimide, sodium phthalimide, and the like, in an organicsolvent such as DMF, DMSO, acetonitrile, and the like, preferably, at anelevated temperature in the range of from 50° C. to about 200° C., morepreferably, at about reflux temperature, to yield the correspondingcompound of formula (XX).

The compound of formula (XX) is reacted with N₂H₄, a known compound, inan organic solvent such as ethanol, methanol, and the like, preferably,at an elevated temperature in the range of from about 50° C. to about100° C., more preferably, at about reflux temperature, and the like, toyield the corresponding compound of formula (Xd).

One skilled in the art will recognize that compounds of formula (X)wherein

is selected from

may be similarly prepared according to known methods or for example,according to the processes outlined in Schemes 2 through 5 above, byselecting and substituting the corresponding naphthyl-fused compoundsfor the benzo-fused starting materials.

One skilled in the art will further recognize that wherein a singleenantiomer (or a mixture of enantiomers wherein one enantiomer isenriched) of a compound of formula (X) is desired, the above processesas described in Schemes 1 through 5 may be applied by substituting thecorresponding single enantiomer (or mixture of enantiomers wherein oneenantiomer is enriched) for the appropriate starting material.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) with a pharmaceuticallyacceptable carrier. Pharmaceutical compositions containing one or moreof the compounds of the invention described herein as the activeingredient can be prepared by intimately mixing the compound orcompounds with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending upon the desired route of administration(e.g., oral, parenteral). Thus for liquid oral preparations such assuspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,stabilizers, coloring agents and the like; for solid oral preparations,such as powders, capsules and tablets, suitable carriers and additivesinclude starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like. Solid oral preparations mayalso be coated with substances such as sugars or be enteric-coated so asto modulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared utilizing aqueous carriers along withappropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.1-1000 mg and maybe given at a dosage of from about 0.01-200.0 mg/kg/day, preferably fromabout 0.1 to 100 mg/kg/day, more preferably from about 0.5-50 mg/kg/day,more preferably from about 1.0-25.0 mg/kg/day, more preferably fromabout 0.5-10.0 mg/kg/day, most preferably from about 1.0 to about 5.0mg/kg/day, or any range therein. The dosages, however, may be varieddepending upon the requirement of the patients, the severity of thecondition being treated and the compound being employed. The use ofeither daily administration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 1000 mgof the active ingredient of the present invention. The tablets or pillsof the novel composition can be coated or otherwise compounded toprovide a dosage form affording the advantage of prolonged action. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer whichserves to resist disintegration in the stomach and permits the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of material can be used for such enteric layers or coatings,such materials including a number of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating depression described in the present invention mayalso be carried out using a pharmaceutical composition comprising any ofthe compounds as defined herein and a pharmaceutically acceptablecarrier. The pharmaceutical composition may contain between about 0.1 mgand 1000 mg, preferably about 50 to 500 mg, of the compound, and may beconstituted into any form suitable for the mode of administrationselected. Carriers include necessary and inert pharmaceuticalexcipients, including, but not limited to, binders, suspending agents,lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.Compositions suitable for oral administration include solid forms, suchas pills, tablets, caplets, capsules (each including immediate release,timed release and sustained release formulations), granules, andpowders, and liquid forms, such as solutions, syrups, elixers,emulsions, and suspensions. Forms useful for parenteral administrationinclude sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of depression is required.

The daily dosage of the products may be varied over a wide range from0.01 to 150 mg/kg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250, 500 and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Aneffective amount of the drug is ordinarily supplied at a dosage level offrom about 0.01 mg/kg to about 1500 mg/kg of body weight per day.Preferably, the range is from about 0.1 to about 100.0 mg/kg of bodyweight per day, more preferably, from about 0.5 mg/kg to about 50 mg/kg,more preferably, from about 1.0 to about 25.0 mg/kg of body weight perday. The compounds may be administered on a regimen of 1 to 4 times perday.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trailsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

EXAMPLE 1 ((3,4-Dihydro-2H-benzo[b][1,4]dioxepin-3-yl)methyl)sulfamide(Compound #3)

Catechol (5.09 g, 46.2 mmol) and potassium carbonate were combined inacetonitrile and heated to reflux for one hour.2-Chloromethyl-3-chloro-1-propene (5.78 g, 46.2 mmol) was added and thereaction was continued at reflux for 24 hours. The solution was cooledto room temperature and filtered. The filtrate was evaporated and theresidue was diluted with water and extracted with diethyl ether (3×).The combined organic solution was dried over MgSO₄ and concentrated.Chromatography (2% ethyl ether in hexane) yielded3-methylene-3,4-dihydro-2H-benzo[b][1,4]dioxepine as a colorless oil.

MS (ESI): 163.2 (M+H⁺)

¹H NMR (300 MHz, CDCl₃), δ: 6.94 (m, 4H), 5.07 (s, 2H), 4.76 (s, 4H).

3-Methylene-3,4-dihydro-2H-benzo[b][1,4]dioxepine (5.00 g, 30.8 mmol)was dissolved in dry THF (100 mL). Borane-THF (1.0 M in THF, 10.3 mL)was added at 0° C. The reaction was stirred at RT for 5 hours.Aminosulfonic acid (6.97 g, 61.6 mmol) was added. The reaction washeated to reflux overnight. The reaction was cooled to room temperatureand aqueous sodium hydroxide (3.0 M, 100 mL) was added. The solution wasextracted with ethyl acetate (3×100 mL). The combined organic solutionwas dried over MgSO₄. The solution was concentrated under vacuum andpurified by chromatography (2% to 8% methanol in dichloromethane) toyield ((3,4-dihydro-2H-benzo[b][1,4]dioxepin-3-yl)methyl)amine as acolorless oil.

MS (ESI): 180.1 (M+H⁺)

¹H NMR (300 MHz, DMSO), δ: 6.92 (m, 4H), 4.21 (m, 2H), 4.07 (m, 2H),3.33 (broad, 2H), 3.16 (d, J=4 Hz, 1H), 2.72 (d, J=4 Hz, 1H), 2.30 (m,1H).

((3,4-Dihydro-2H-benzo[b][1,4]dioxepin-3-yl)methyl)amine (2.90 g, 16.2mmol) and sulfamide (3.11 g, 32.4 mmol) were combined in dry dioxane (60ml) and heated to reflux overnight. Chloroform was added and theprecipitate was removed by filtration. The filtrate was concentratedunder vacuum and purified by chromatography (2% to 8% acetone indichloromethane) to yield the title compound as an off-white solid.

258.8 (M+H⁺)

¹H NMR (300 MHz, DMSO), δ: 6.92 (m, 4H), 6.71 (broad, 1H), 6.59 (broad,2H), 4.19 (m, 2H), 4.04 (m, 2H), 3.00 (m, 2H), 2.39 (m, 1H).

EXAMPLE 2 N-(2,3-Dihydro-benzo[1.4]dioxin-2-ylmethyl)-sulfamide(Compound #1)

Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (4.4 g, 26 mmol) andsulfamide (5.1 g, 53 mmol) were combined in 1,4 dioxane (100 mL) andrefluxed for 2 h. The reaction was cooled to room temperature and asmall amount of solid was filtered and discarded. The filtrate wasevaporated in vacuo and the residue was purified using flash columnchromatography (DCM:Methanol—10:1) to yield a white solid. The solid wasrecrystallized from DCM to yield the title compound as a white solid.

mp: 97.5-98.5° C.

Elemental Analysis: Anal Calc: C, 44.25; H, 4.95; N, 11.47; S, 13.13Anal Found: C, 44.28; H, 4.66; N, 11.21; S, 13.15

H¹ NMR (DMSO d6) δ 6.85 (m, 4H), 6.68 (bd s, 3H, NH), 4.28 (m, 2H), 3.97(dd, J=6.9, 11.4 Hz, 1H), 3.20 (m, 1H), 3.10 (m, 1H).

EXAMPLE 3

(Benzo[1,3]-dioxol-2-ylmethyl)sulfamide (Compound #2)

Catechol (10.26 g, 93.2 mmol), sodium methoxide (25% by weight inmethanol, 40.3 g, 186 mmol), and methyl dichloroacetate (13.3 g, 93.2mmol) were combined in dry methanol (100 mL). The solution was heated toreflux overnight. The reaction was cooled to room temperature, acidifiedby addition of concentrated hydrochloric acid and then reduced in volumeunder vacuum to about 50 mL. Water was added and the mixture wasextracted with diethyl ether (3×100 mL). The combined organic solutionwas dried with MgSO₄, concentrated to a brown solid, and chromatographed(2% ethyl acetate in hexane) to yield benzo[1,3]dioxole-2-carboxylicacid methyl ester as a colorless oil.

MS (ESI): 195.10 (M+H⁺).

¹H NMR (300 MHz, CDCl₃), δ: 6.89 (broad, 4H), 6.29 (s, 1H), 4.34 (q, J=7Hz, 2H), 1.33 (t, J=7 Hz, 3H).

To benzo[1,3]dioxole-2-carboxylic acid methyl ester (7.21 g, 40.0 mmol)was added ammonium hydroxide (29% in water, 10 mL) and enoughacetonitrile to make the mixture homogeneous (˜5 mL). The solution wasstirred for two hours at room temperature and then distilled water wasadded. Benzo[1,3]dioxole-2-carboxylic acid amide precipitated as a whitesolid and was collected by filtration and used without furtherpurification.

MS (ESI): 160.00 (M+H⁺)

¹H NMR (300 MHz, DMSO), δ: 7.99 (s, broad, 1H), 7.72 (s, broad, 1H),6.94 (m, 2H) 6.86 (m, 2H), 6.30 (s, 1H).

Benzo[1,3]dioxole-2-carboxylic acid amide (5.44 g, 32.9 mmol) wasdissolved in tetrahydrofuran (THF, 100 mL). Lithium aluminum hydride(LAH, 1M in THF, 39.5 mL, 39.5 mmol) was added slowly to the solution atroom temperature. The reaction was stirred at room temperature for 24hours. Distilled water was added to destroy the excess LAH. Aqueoussodium hydroxide (3.0 M, 100 mL) was added and the solution wasextracted with ethyl acetate (3×100 mL). The combined organic solutionwas washed with water and dried over MgSO₄. The solvent was evaporatedto yield C-benzo[1,3]dioxol-2-yl-methylamine as a colorless oil.

MS (ESI): 152.1 (M+H⁺)

¹H NMR (300 MHz, CDCl₃), δ: 6.87 (m, 4H), 6.09 (t, J=4 Hz, 1H), 3.13 (d,J=4 Hz, 2H)

C-Benzo[1,3]dioxol-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfamide(3.74 g, 38.9 mmol) were combined in dry dioxane (50 mL) and thesolution was heated to reflux overnight. The reaction was concentratedand the residue was chromatographed (2% to 10% acetone indichloromethane) to yield the title compound as a white solid.

MS (ESI): 230.0 (M+H⁺)

¹H NMR (300 MHz, CDCl₃), δ: 6.87 (m, 4H), 6.25 (t, J=4 Hz, 1H), 4.79(broad, 1H), 4.62 (broad, 1H), 3.64 (d, J=4 Hz, 2H).

EXAMPLE 4 (2S)-(−)-N-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide(Compound #4)

Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol)were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10mol) was added and the reaction was stirred at 60° C. for 24 h. Thereaction was cooled to room temperature and diluted with ice water (1 L)and extracted with diethyl ether (4 times). The combined organicsolution was washed 3 times with 10% potassium carbonate, once withwater, once with brine and evaporated in vacuo to yield a white solidwhich was purified by flash column chromatography (DCM:Methanol—50:1) toyield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid.

The solid (13.3 g, 68 mmol) was dissolved in pyridine (85 mL) cooled to0° C., p-toluenesulfonyl chloride (13.0 g, 68 mmol) was added and thereaction mixture stirred at room temperature for 20 h. The reaction wasdiluted with diethyl ether (1 L) and 1N HCl (1.2 L). The organic layerwas separated and washed 2 times with 1N HCl (500 mL), 4 times withwater (150 mL), once with brine, dried (MgSO₄) and evaporated in vacuoto yield a white solid which was purified by flash column chromatography(Hept:EA—2:1) to yield toluene-4-sulfonic acid(2S)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester as a white solid.

The white solid was combined with potassium phthalimide (14.4 g, 78mmol) in DMF (250 mL) and heated to reflux for 1 h, cooled to roomtemperature and poured into vigorously stirring water (1.5 L) andstirred 30 min. White solid was filtered and the solid was washedseveral times with water, 2% NaOH, and water again and let air dry toyield a(2S)-2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione aswhite powdery solid.

The powdery white solid was combined with hydrazine (2.75 g, 86 mmol) inEtOH (225 mL) and heated at reflux for 2 h, cooled to room temperatureand 1N HCl added to pH 1.0 and stirred for 15 min. White solid wasfiltered and washed with fresh EtOH (solid discarded) and the filtratewas evaporated in vacuo to a solid, which was partitioned betweendiethyl ether and dilute aqueous NaOH. The diethyl ether solution wasdried (Na₂SO₄) and evaporated in vacuo to a yield a light yellow oil.The oil was purified by flash column chromatography (DCM:MeOH—10:1) toyield an oil. A portion of the oil (4.82 g, 29 mmol) in 2-propanol (250mL) was treated with 1N HCl (30 mL) and heated on steambath untilhomogeneous and then let cool to room temperature. After 3 h, themixture was ice cooled for 2 h. A white flaky solid (the correspondingHCl salt of (2S)-C-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-methylamine) wasfiltered off and then recrystallized again from 2-propanol to yield awhite solid.

[α]_(D)=−69.6 (c=1.06, EtOH)

The white solid was partitioned between DCM and dilute NaOH, and the DCMwas dried (NaSO₄) and evaporated in vacuo to yield(2S)-C-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-methylamine as an oil.

[α]_(D)=−57.8 (c=1.40, CHCl₃)

The oil (2.1 g, 12.7 mmol) and sulfamide (2.44 g, 25.4 mmol) wererefluxed in dioxane (75 mL) for 2 h and the crude product was purifiedby flash column chromatography (DCM:MeOH 10:1) to yield a white solid,which was recrystallized from DCM to yield the title compound as a whitecrystalline solid.

mp 102-103° C.

[α]_(D)=−45.1° (c=1.05, M);

¹H NMR (DMSO-d6) δ 6.86 (m, 4H), 6.81 (bd s, 3H, NH), 4.3 (m, 2H), 3.97(dd, J=6.9, 11.4 Hz, 1H), 3.20 (dd, J=5.5, 13.7 Hz, 1H), 3.10 (dd,J=6.9, 13.7 Hz, 1H)

Elemental Analysis: Anal Calc: C, 44.25; H, 4.95; N, 11.47; S, 13.13Anal Found: C, 44.20; H, 4.69; N, 11.40; S, 13.22.

EXAMPLE 5N-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-N′,N′dimethylsulfamide(Compound #6)

Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (8.25 g, 5.0 mmol)and triethylamine (1.52 g, 15 mmol) were combined in DMF (10 mL) andcooled in an ice bath as dimethylsulfamoyl chloride (1.44 g, 10 mmol)was added. The reaction mixture was then stirred for 3 hr with continuedcooling. The reaction mixture was partitioned between ethyl acetate andwater, and the ethyl acetate solution was washed with brine, dried(MgSO₄) and evaporated in vacuo to yield an oil. The oil was purifiedusing flash column chromatography (ethyl acetate:Heptane—1:1) to yield awhite solid, which was recrystallized (ethyl acetate/Hexane) to yieldthe title compound as a white floccular solid.

mp 76-78° C.

MS 273 (MH⁺)

Elemental Analysis: Anal Calc: C, 48.52; H, 5.92; N, 10.29; S, 11.78Anal Found: C, 48.63; H, 5.62; N, 10.20; S, 11.90

¹H NMR (CDCl₃) δ 6.87 (m, 4H), 4.59 (bd m, 1H, NH), 4.35 (m, 1H), 4.27(dd, J=2.3, 11.4 Hz, 1H), 4.04 (dd, J=7.0, 11.4, 1H), 3.36 (m, 2H), 2.82(s, 6H).

EXAMPLE 6 N-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-N-methylsulfamide(Compound #7)

Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (825 mg, 5 mmol) wasdissolved in ethyl formate (15 mL), refluxed for 30 min and evaporatedin vacuo to yield N-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-formamideas an oil.

The oil in diethyl ether (25 mL) was treated with 1M LAH in THF (9.0 mL,9.0 mmol) at 0° C. and stirred for 5 h at room temperature. The reactionwas cooled in an ice bath and quenched with water (0.50 mL), followed by3 N NaOH (0.50 mL) and water (0.50 mL). The mixture was then stirred atroom temperature for 1 h. Solid was filtered and the filtrate wasevaporated in vacuo to yield a residue which was partitioned between 1NHCl and diethyl ether. The aqueous phase was basified with 1N NaOH andextracted with diethyl ether. The organic phase was dried (MgSO₄) andevaporated in vacuo to yield(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-methyl-amine as an oil.

MS 180 (MH⁺)

¹H NMR (CDCl₃) δ 6.85 (m, 4H), 4.30 (m, 2H), 4.02 (dd, J=7.9, 11.6 Hz,1H), 2.85 (m, 2H), 2.50 (s, 3H)

The oil (380 mg, 2.1 mmol) and sulfamide (820 mg, 8.5 mmol) werecombined in dioxane (15 mL), refluxed for 1.5 h and evaporated in vacuoto yield a crude residue. The residue was purified via columnchromatography (ethyl acetate/Heptane 1:1) and the resultant solid wasrecrystallized from ethyl acetate/Hexane to yield the title compound asa white solid.

mp 97-98° C.

MS 257 (M⁻¹)

Elemental Analysis: Anal Calc: C, 46.50; H, 5.46; N, 10.85; S, 12.41Anal Found: C, 46.48; H, 5.65; N, 10.90; S, 12.07

¹H NMR (CDCl₃) δ 6.86 (m, 4H), 4.52 (bs, 2H), 4.46 (m, 1H), 4.29 (dd,J=2.3, 11.5 Hz, 1H), 4.05 (dd, J=6.5, 11.5 Hz, 1H), 3.51 (dd, J=6.7,14.9 Hz, 1H), 3.40 (dd, J=5.9, 14.9 Hz, 1H), 2.99 (s, 3H).

EXAMPLE 7(2S)-(−)-N-(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide(Compound #8)

Following the procedure outlined in Example 4 above, 4-chlorocatecholwas reacted to yield a mixture of(2S)-C-(7-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methylamine and(2S)-C-(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methylamine (ca. 3:1ratio of 6-chloro:7-chloro isomers by RP HPLC).

The mixture was dissolved in 2-propanol (100 mL) and 1N HCl in diethylether was added until pH=1.0 was attained. The hydrochloride salt thatprecipitated was filtered (2.65 g) and re-crystallized from methanol/IPAto yield white crystals. The white crystals were partitioned between DCMand dilute NaOH. The DCM was dried and evaporated in vacuo to yieldpurified (2S)-C-(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methylamineas an oil.

[α]_(D)=−67.8 (c=1.51, CHCl₃)

The oil (7.75 mmol) and sulfamide (1.50 g, 15.5 mmol) were combined indioxane (50 mL) and refluxed for 2.0 h, cooled to room temperature andevaporated in vacuo to yield a solid. The product was purified via flashcolumn using DCM/methanol 20:1 to yield the title compound as a whitesolid.

MS 277 (M⁻¹)

[α]_(D)=−59.9°(c=1.11, M)

¹H NMR (CDCl₃) δ 6.90 (d, J=2.2 Hz, 1H), 6.81 (m, 2H), 4.76 (m, 1H),4.55 (s, 2H), 4.40 (m, 1H), 4.29 (dd, J=2.4, 11.5 Hz, 1H), 4.05 (dd,J=7.1, 11.5 Hz, 1H), 3.45 (m, 2H)

Elemental Analysis: Anal Calc: C, 38.78; H, 3.98; N, 10.05 Anal Found:C, 38.80; H, 3.67; N, 9.99.

The filtrates of the crystallized hydrochloride salt of(2S)-C-(6-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methylamine preparedabove were recovered (ca. 1:1 of 6-chloro:7-chloro isomers) andevaporated in vacuo to yield a solid, which was partitioned between DCM(200 mL) and dilute NaOH (0.5 M, 50 mL). The DCM solution was washedonce with brine, dried (Na₂SO₄) and evaporated in vacuo to yield an oil,which was purified via reverse phase HPLC (10-50% ACN with 0.16% TFA inwater with 0.20% TFA) to yield(2S)-C-(7-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methylamine as aresidue.

The residue was combined with sulfamide (0.90 g, 9.4 mmol) in dioxane(25 mL) and refluxed for 2.5 h, cooled to room temperature andevaporated in vacuo to yield an oil. The oil was purified by flashcolumn chromatography using DCM/methanol—10:1 to yield(2S)-(−)-N-(7-Chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamideas a white solid.

MS 277 (M⁻¹)

¹H NMR (CDCl₃/CD₃OD) δ 6.88 (d, J=0.7 Hz, 1H), 6.81 (m, 2H), 4.37 (m,1H), 4.30 (dd, J=2.3, 11.6 Hz, 1H), 4.04 (dd, J=7.0, 11.6 Hz, 1H), 3.38(m, 2H).

EXAMPLE 8

Chroman-2-ylmethylsulfamide (Compound #10)

Chroman-2-carboxylic acid (4.5 g, 25 mmol) and HOBT (3.86 g, 25 mmol)were combined in DCM (40 mL) and DMF (10 mL). Dimethylaminopropylethylcarbodiimide (EDC, 4.84 g, 25 mmol) was added at room temperatureand the reaction mixture was stirred for 30 min. Ammonium hydroxide(2.26 mL, 33.4 mmol) was added and the reaction mixture was stirred for16 h. The reaction mixture was diluted with DCM (50 mL) and water (50mL) and the pH of the mixture was adjusted to about pH=3.0 with 1N HCl.The DCM was separated and the aqueous phase extracted twice with DCM.The combined DCM phase was dried (Na₂SO₄) and evaporated in vacuo toyield an oil, which was purified with flash column chromatography (ethylacetate) to yield an oil.

The oil (5.35 g, 30 mmol) in THF (90 mL) was stirred as 1M LAH in THF(36 mL, 36 mmol) was added and the reaction mixture was then stirred atroom temperature for 20 h. The reaction was quenched with water, stirredfor 2 hours, the solution decanted, dried (Na₂SO₄) and evaporated invacuo to yield C-chroman-2-yl-methylamine as an oily amine.

The oily amine (1.63 g, 10 mmol) and sulfamide (1.92 g, 20 mmol) werecombined in dioxane (50 mL) and brought to reflux for 2 h. The solutionwas cooled and evaporated in vacuo to yield an oil, which was purifiedvia column chromatography (DCM:Methanol 10:1) to yield a white solid.The solid was recrystallized from ethyl acetate/hexane to yieldchroman-2-ylmethylsulfamide as a white solid.

mp 100-101° C.

MS 241 (M⁻¹)

Elemental Analysis: Anal Calc: C, 49.57; H, 5.82; N, 11.56; S, 13.23Anal Found: C, 49.57; H, 5.80; N, 11.75; S, 13.33.

EXAMPLE 9 2-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-ethylsulfamide (Compound#16)

Potassium cyanide (2.05 g, 31.5 mmol) was added to 2-bromomethyl-(2,3dihydrobenzo[1,4]dioxine) (6.87 g, 30 mmol) in DMSO (90 mL) and stirredat ambient temperature for 20 h. The reaction mixture was then dilutedwith water (250 mL) and extracted twice with diethyl ether. The diethylether was washed with water, then washed twice with brine, dried(Na₂SO₄) and evaporated in vacuo to yield 2-cyanomethyl-(2,3dihydrobenzo[1,4]dioxine) as a white solid.

¹H NMR (CDCl₃) δ 6.89 (m, 4H), 4.50 (m, 1H), 4.31 (dd, J=2.3, 11.5 Hz,1H), 4.08 (dd, J=6.2, 11.6 Hz, 1H), 2.78 (d, J=6.1, Hz, 2H)

The 2-cyanomethyl-(2,3 dihydrobenzo[1,4]dioxine) was dissolved in THF(50 mL) and 1M BH₃ in THF (80 mL, 80 mmol) was added and the reactionmixture refluxed for 5 h, then stirred at ambient temperature for 16 h.With ice bath cooling, 2N HCl was added until pH=1.0 was achieved. Thereaction mixture was then stirred for 1 h at room temperature andevaporated in vacuo to yield an oil. The oil was partitioned between 3NNaOH and diethyl ether, and the diethyl ether solution was washed withbrine, dried (Na₂SO₄) and evaporated in vacuo to yield crude 2-(2,3dihydrobenzo[1,4]dioxin-2-yl)ethylamine.

MS (M+H)⁺180.

The crude 2-(2,3 dihydrobenzo[1,4]dioxin-2-yl)ethylamine in dioxane (100mL) was combined with sulfamide (3.0 g, 31 mmol) and heated to refluxfor 2 h. The solution was cooled and evaporated in vacuo to yield anorange solid, which was purified by column chromatography(DCM:MeOH—10:1) to yield a white solid. The solid was re-crystallizedfrom DCM to yield the title compound as a solid.

MS (M−1) 257

MP 101-103° C. (corr)

¹H NMR (CDCl₃): δ6.86 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 4.30 (m, 2H),3.94 (dd, J=7.4, 11.3 Hz, 1H), 3.43 (dd, J=6.4, 12.9 Hz, 2H), 1.94 (dd,J=6.5, 12.9, 2H).

Elemental Analysis: Measured: C, 46.48; H, 5.60; N, 10.81; S, 12.41Calculated: C, 46.50; H, 5.46; N, 10.85; S, 12.41

EXAMPLE 10 (2S)-(−)-N-(6,7Dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide (Compound#29)

4,5 Dichloroatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48mmol) were stirred in DMF (200 mL). (2R)-Glycidyl tosylate (9.12 g, 40mmol) was added and the reaction mixture was stirred at 60° C. for 24 h.The reaction mixture was cooled to room temperature and then dilutedwith ice water (600 mL) and extracted with diethyl ether (4 times). Thecombined organic solution was washed 3 times with 10% potassiumcarbonate, twice with brine, dried (MgSO₄) and evaporated in vacuo toyield a viscous oil of(2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol.

The (2S)-2-(6,7 dichloro-2,3-dihydro-benzo[1,4]dioxine) methanol oil(6.4 g, 27 mmol) was dissolved in pyridine (50 mL) cooled to 0° C. Then,p-toluenesulfonyl chloride (5.2 g, 27 mmol) was added and the reactionmixture was stirred at room temperature for 20 h. The reaction mixturewas diluted with diethyl ether and 1N HCl (750 mL) and the organic layerwas separated and washed 2 times with 1N HCl (250 mL), once with water(150 mL), twice with brine, dried (MgSO₄) and evaporated in vacuo toyield light yellow solid of toluene-4-sulfonic acid(2S)-6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester.

¹H NMR (CDCl3): δ 7.79 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 6.94(s, 1H), 6.83 (s, 1H), 4.37 (m, 1H), 4.2 (m, 3H), 4.03 (dd, J=6.3, 11.7Hz, 1H), 2.47 (s, 3H).

Toluene-4-sulfonic acid(2S)-6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (8.0 g,20.5 mmol) was combined with potassium phthalimide (6.1 g, 33 mmol) inDMF (75 mL) and heated to reflux for 1 h, cooled to room temperature andpoured into vigorously stirring water (0.5 L) and then stirred 30 min.White solid was filtered and the solid was washed several times withwater, 2% NaOH, and water again and then let air dry to yield(2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione(6.0 g, 80%) as a white powdery solid.

The white powdery solid was combined with hydrazine (1.06 g, 33 mmol) inEtOH (80 mL) and heated at reflux for 2 h, then cooled to roomtemperature. 1N HCl was added to adjust the reaction mixture's pH to pH1.0 and the reaction mixture was then stirred for 15 min. White solidwas filtered and washed with fresh EtOH (solid discarded) and thefiltrate was evaporated in vacuo to a solid, which was partitionedbetween diethyl ether and dilute aqueous NaOH. The diethyl ethersolution was dried (Na₂SO₄) and evaporated in vacuo to a yield a viscousoil of (2S)-2-aminomethyl-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxine).

¹H NMR (CDCl3): δ 6.98 (s, 1H), 6.96 (s, 1H), 4.25 (dd, J=2.0, 11.2 Hz,1H), 4.15 (m, 1H), 4.0 (m, 1H), 2.97 (d, J=5.5 Hz, 2H)

A portion of the oil (3.8 g, 16 mmol) and sulfamide (3.1 g, 32.4 mmol)were refluxed in dioxane (100 mL) for 2 h and the crude product waspurified by flash column chromatography (DCM:MeOH 20:1) to yield thetitle compound as a white solid, which was recrystallized from ethylacetate/hexane to yield the title compound as a white crystalline solid.

MS [M−H]⁻311.0

mp 119-121° C.

[α]_(D)=−53.4° (c=1.17, M)

¹H NMR (DMSO-d6): δ 7.22 (s, 1H), 7.20 (s, 1H), 6.91 (bd s, 1H), 6.68(bd s, 2H), 4.35 (m, 2H), 4.05 (dd, J=6.5, 11.5 Hz, 1H), 3.15 (m, 2H)

Elemental Analysis:

Elemental Analysis: Measured: C, 34.52; H, 3.22; N, 8.95; Cl, 22.64; S,10.24 Calculated: C, 34.64; H, 2.68; N, 8.87; Cl, 22.94; S, 10.35.

EXAMPLE 11(2S)-(−)-N-(7-Amino-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide(Compound #36)

(2S)-(−)-N-(2,3-Dihydro-7-nitro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide(1.2 g, 4.15 mmol), was prepared from 4-nitrocatechol according to theprocess outlined in Example 4. The(2S)-(−)-N-(2,3-Dihydro-7-nitro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide,was then combined with 10% Pd/C in methanol (120 mL) and shaken underhydrogen atmosphere (39 psi) at room temperature for 3 h. The solidswere filtered and washed with 10% M in DCM and the filtrate wasevaporated in vacuo to yield crude product. The crude product wasdissolved in 0.2 N HCl (25 mL), frozen and lyophilized to yield thetitle compound as a white flaky solid, as the correspondinghydrochloride salt.

MS (M+H)⁺260

¹H NMR (DMSO d6): δ10.2 (bd s, 3H), 6.86 (m, 1H), 6.85 (s, 1H), 6.74(dd, J=2.5, 8.4 Hz, 1H), 4.22 (m, 2H), 3.88 (dd, J=6.7, 11.4 Hz, 1H),3.04 (m, 2H)

EXAMPLE 12(2S)-(−)-N-(7-Methyl-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide

(Compound #19)

Title compound was prepared according to the procedure described inExample 4 above, starting with 4-methylcatechol, to yield a white solid,which was recrystallized from ethyl acetate/hexane to yield the titlecompound as a white solid.

MS [M−H]⁻257

¹H NMR (CDCl3): δ 6.76 (m, 1H), 6.66 (m, 2H), 4.80 (m, 1H), 4.57 (bd s,1H), 4.40 (m, 1H), 4.28 (m, 1H), 4.03 (dd, J=6.9, 11.4 Hz, 1H), 3.45 (m,2H), 2.25 (s, 3H).

Elemental Analysis Calculated: C, 46.50; H, 5.46; N, 10.85; S, 12.41Found: C, 46.65; H, 5.60; N, 10.84; S, 12.61.

EXAMPLE 13 AKR/J Obese Mice In Vivo Assay

AKR/J mice are known in the art to be susceptible to diet-inducedobesity. (Rossmeisl M, Rim J S, Koza R A, Kozak L P. Diabetes. 2003August; 52(8):1958-66.)

Male AKR/J mice (˜20 gram) at 4-5 weeks of age (Jackson Laboratories,Bar Harbor, Me.) were housed individually in a shoe-box cage at 21° C.with a 12-h light-dark cycle. The mice were fed with a high fat diet for8 weeks to induce obesity. The composition of the diet by energy was 45%energy as fat, 20% as protein, and 35% as carbohydrate (Research Diets,D12451, New Brunswick, N.J.).

Obese mice with body weights between 35 and 46 grams were selected forthe studies. Mice were randomized according to body weight intotreatment groups at 13 weeks of age. The mice were orally gavaged oncedaily (0.2 ml at 1500-1700 hour) with vehicle control (0.5%methylcellulose, pH7.4) or vehicle containing Compound #8 (300 mg/kg).The body weights and food intake of the mice were monitored every fewdays. On day 11, the mice were anaesthetized with sodium pentobarbital(1 ml/kg, i.p, Sleepaway, Fort Dodge, Iowa). White adipose tissue (WAT)(retroperitoneal fat) and skeletal muscle (gastrocnemius and soleusmuscle) were dissected and weighed.

Data shown below are expressed as mean and standard error calculatedusing 9-10 mice per treatment group. The 2 tailed Student's t-Tests wereused for statistic analysis. All animal studies complied with theguideline of the Institutional Animal Care and Use Committee.

After 10-day treatment, Compound #8 treated mice showed greater weightloss compared to vehicle treated mice. The weight loss was accompaniedwith the loss of the white adipose tissue—there was a 26.6% reduction ofretroperitoneal fat in Compound #8 treated mice relative to vehicletreated mice, with no significant changes in skeletal muscle mass. Thusthe fat to lean mass ratio (white adipose tissue/skeletal muscle)decreased by 16.8% in Compound #8 treated mice compared to vehicletreated mice (vehicle: 8.9±0.4 vs Compound #8: 7.4±0.5, p<0.05). Areduction of food intake was also observed from day 4 to day 10 inCompound #8 treated mice relative to control animals. Compound #8 wasalso measured to delay gastric emptying at a statistically significantlevel (p<0.05).

A summary of the data for vehicle and Compound #8 treated mice measuringweight, food intake, fat and muscle mass as shown in Table 4, below.TABLE 4 Obese Mice In Vivo Results Skeletal Weight Food IntakeRetroperitoneal Muscle Loss (g) (g) Day 4-10 Fat Weight (g) Weight (g)Vehicle −0.7 ± 0.31 18.8 ± 0.67 0.64 ± 0.04 0.31 ± 0.01 Compound −3.3 ±0.34 16.2 ± 0.68 0.47 ± 0.04 0.30 ± 0.01 #8 p < 0.01 p < 0.05 p < 0.05

Thus, the data show that Compound #8 was effective at promoting weightloss, wherein the loss was in fat rather than muscle mass and wasfurther effective in decreasing food intake (i.e. suppressing appetite).

EXAMPLE 14

Obesity In Vivo Assays

Compound #8 was suspended in 0.5% Methocel using a hand held homogenizerto reduce the particle size and a magnetic stir bar and stir plate tokeep the particles homogeneously suspended throughout the dosing period.0.5% Hydroxypropyl Methylcellulose (Methocel) used as vehicle/control.

Male AKR/J mice weighing between 35 to 46 grams were used for weightloss studies. AKR/J mice are susceptible to diet-induced obesity. MaleAKR/J mice (average body weight of about 20 grams) at 4 to 5 weeks ofage (obtained from Jackson Laboratories, Bar Harbor, Me.) were grouphoused, five per cage, in a shoebox cage at 21° C. with a 12 h lightdark cycle. All of the mice were quarantined for a period of one weekbefore transfer to the animal procedure room. The mice were fed a highfat diet for 8 weeks to induce obesity. The composition of the diet byenergy was 45% energy as fat, 20% as protein, and 35% as carbohydrate(obtained from Research Diets, D12451, New Brunswick, N.J.). As anon-obese control, an additional group of mice that were age- andweight-matched was fed with a low fat diet (obtained from ResearchDiets, D12450B, New Brunswick, N.J.). Only mice that developed obesity,defined as a body weight between 35 and 46 grams, were selected for theweight loss studies. Animals were separated and single housed at leastthree days prior to the drug treatments to allow acclimation to the newsurroundings.

The assay comprised two separate studies: In the first study, 10 micewere given vehicle control of 0.5% Methocel; 10 mice were treated with300 mg/kg Compound #8 in vehicle; and 10 mice were dosed as positivecontrol with 10 mg/kg sibutramine (a weight loss agent) in vehicle. Inthe second study, 48 mice were allocated into 4 treatment groups of 12mice each. The four groups were then treated with 0.5% Methocel(vehicle), 10 mg/kg Compound #8, 30 mg/kg Compound #8, and 100 mg/kgCompound #8 in vehicle, respectively.

The mice were orally gavaged once daily (at 1500-1700 hour) with vehiclecontrol (0.5% methocel, pH7.4) or vehicle containing Compound #8 for 10days. The dosing volume was 5 mL/kg body weight (0.2 mL for 40 grammice). Body weight and food intake of mice were monitored periodicallythroughout the studies. On Day 11, the mice were fasted for 4 hr duringlight cycle (food was removed 0600-1000 hour). A necropsy was done 18hours after last dosing. The mice were anaesthetized with sodiumpentobarbital (1 ml/kg, intraperitoneal [i.p.] injection, SleepAway,Fort Dodge, Iowa) and blood was drawn via cardiac puncture using an 1 mLsyringe and collected into heparinized tubes. White adipose tissues(WAT) (retroperitoneal and inguinal fat pads), brown adipose tissue(BAT) and skeletal muscles (gastrocnemius and soleus muscle) and stomachcontents were dissected and weighed. Plasma samples were obtained bycentrifuging whole blood at 2000˜3000 g for 10˜20 minutes at 4° C. andstored at −20° C. for further measurement of insulin, HDL, LDL, andtotal cholesterol and triglyceride.

Blood glucose levels were measured with a glucometer (OneTouchUltraSmart, Lifescan, Milpitas, Calif.) after collecting two microlitersof blood through tail puncture. Plasma insulin concentrations weremeasured by using rat/mouse insulin enzyme-linked immunosorbent assay(ELISA) kit (EZRMI-13K, LINCO Research, St. Charles, Mo.). Blood sampleswere diluted 1:4 in charcoal stripped mouse serum that was included inthe ELISA kit. The rest of the procedure followed the manufacturersinstruction. The total fluorescence was detected using an Orion 1Microplate Luminometer (Berthold Detection Systems, Pforzheim, Germany).Plasma total cholesterol, high density lipoprotein (HDL), low densitylipoprotein (LDL) and triglyceride concentrations were measured by usinga Bayer ADVIA 1650 blood chemistry analyzer (Bayer HealthCare LLC,Diagnostic Division, Tarrytown, N.Y.). According to manufacturersprotocol, cholesterol measurement was an enzymatic method utilizingcholesterol esterase and cholesterol oxidase conversion followed by aTrinder endpoint; Elimination/catalase method was used for HDL and LDLmeasurement; an enzymatic method with a Trinder endpoint was used fortriglyceride measurement.

Data from the studies was analyzed using the standard two-tailedStudent's t-test and are expressed in the tables below as means andstandard errors. Fat/muscle ratios were calculated as: total weights ofinguinal fat and retroperitoneal fat/muscle weight. Values listed in thetables represent the mean ±SE (n=9˜10).

The average body weight of AKR/J mice before the start of the high fatdiet was 21.7±0.49 g. After eight weeks on the high fat diet, theaverage weight of the mice was 37.6±0.45 g. The mice with greatestweight gain were selected for dosing with Compound #8 or vehicle.

In the first study, and as shown in Table 5 below, mice treated with 300mg/kg of Compound #8 showed significant weight loss, compared withvehicle treated mice after 10 days of dosing. The weight loss effectswere observed 3 days after treatment and lasted until the end of thestudy. Significant suppression of food intake was also found three daysafter treatment with Compound #8 compared to vehicle. In contrast, micetreated with the anti-obesity agent sibutramine lost weight after 3 daystreatment, but showed no difference in weight at the end of the studycompared to control mice. A reduction of food intake in sibutraminetreated mice was also seen from day 0 to Day 3 but not from Day 4through Day 9. Total stomach content, measured at the end of the study,was significantly greater (0.27±0.05 g, p<0.05) with Compound #8treatment compared to vehicle treatment (0.16±0.02 g). TABLE 5 Weightloss (g) Intake of high fat diet (g) Treatment Day 4 Day 8 Day 10 Day0-3 Day 4-7 Vehicle −0.2 ± 0.1 −0.3 ± 0.3 −0.7 ± 0.3 9.3 ± 0.2 12.9 ±0.5 Sibutramine   −2.0 ± 0.2*** −1.2 ± 0.4 −1.2 ± 0.5  6.5 ± 0.3** 14.4± 0.7 Compound #8 −0.3 ± 0.3   −2.5 ± 0.3***   −3.3 ± 0.3*** 10.0 ± 0.4  10.6 ± 0.4* @ 300 mg/kg*p < 0.05,**p < 0.01,***p < 0.001 versus vehicle control, respectively.

Mice treated with Compound #8 also showed reduced white adipose tissueweight compared with vehicle treatment after 10 days of dosing. Thisresulted in a lower ratio of fat to muscle weight in the Compound #8treated group of mice, as shown in Table 6, below. In Table 6 below, theratio of fat to muscle was calculated as: total weights of inguinal fatand retroperitoneal fat/muscle weight. TABLE 6 EpididymalRetroperitoneal Muscle Brown Adipose Ratio Treatment fat (g) fat (g) (g)Tissue (g) (fat/muscle) Vehicle 2.08 ± 0.11  0.64 ± 0.04 0.31 ± 0.010.13 ± 0.01 8.90 ± 0.42 Sibutramine 1.76 ± 0.11* 0.61 ± 0.07 0.31 ± 0.010.14 ± 0.01 7.67 ± 0.59 Compound #8 1.73 ± 0.10*  0.47 ± 0.04* 0.30 ±0.01 0.22 ± 0.09  7.42 ± 0.54* @ 300 mg/kg*p < 0.05 versus vehicle control, respectively.

In the second dose response study, as shown in Table 7 below, there wasno significant (P>0.05) weight loss or food intake suppression in themice treated with 10, 30, and 100 mg/kg of Compound #8. In this study,tissue was not collected and as such values from fat and muscle were notdetermined. TABLE 7 Total intake of high fat Weight loss (g) diet (g)Treatment Day 4 Day 7 Day 10 Day 1-10 Vehicle −0.3 ± 0.1  −0.3 ± 0.2 −0.4 ± 0.2  27 ± 0.5 Compound #8 0.1 ± 0.1 0.2 ± 0.2 0.3 ± 0.3 28 ± 0.5@ 10 mg/kg Compound #8 0.1 ± 0.1 0.0 ± 0.2 −0.4 ±0.2   28 ± 0.5 @ 30mg/kg Compound #8 0.2 ± 0.1 0.2 ± 0.3 0.1 ± 0.2 28 ± 0.6 @ 100 mg/kg

EXAMPLE 15

As a specific embodiment of an oral composition, 100 mg of the Compound#8 prepared as in Example 7 is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size O hardgel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A method for treating obesity, promoting weight loss or suppressingappetite comprising administering to a subject in need thereof, atherapeutically effective amount of a compound of formula (I)

wherein R¹ and R² are each independently selected from the groupconsisting of hydrogen and lower alkyl; R⁴ is selected from the groupconsisting of hydrogen and lower alkyl; a is an integer from 1 to 2;

is selected from the group consisting of

wherein b is an integer from 0 to 4; and wherein c is an integer from 0to 2; each R⁵ is independently selected from the group consisting ofhalogen, lower alkyl and nitro; provided that when

then a is 1; or a pharmaceutically acceptable salt thereof.
 2. Themethod as in claim 1, wherein R¹ and R² are each independently selectedfrom the group consisting of hydrogen and lower alkyl; R⁴ is selectedfrom the group consisting of hydrogen and lower alkyl; a is an integerfrom 1 to 2;

is selected from the group consisting of

wherein b is an integer from 0 to 2; and wherein c is an integer from 0to 1; each R⁵ is independently selected from the group consisting ofhalogen, lower alkyl and nitro; provided that when

then a is 1; or a pharmaceutically acceptable salt thereof.
 3. Themethod as in claim 2, wherein R¹ and R² are each independently selectedfrom the group consisting of hydrogen and lower alkyl; R⁴ is selectedfrom the group consisting of hydrogen and lower alkyl; a is an integerfrom 1 to 2;

is selected from the group consisting of

wherein b is an integer from 0 to 2; and wherein c is 0; each R⁵ isindependently selected from the group consisting of halogen, lower alkyland nitro; provided that when

then a is 1; or a pharmaceutically acceptable salt thereof.
 4. Themethod as in claim 3, wherein R¹ and R² are each independently selectedfrom the group consisting of hydrogen and lower alkyl; R⁴ is selectedfrom the group consisting of hydrogen and methyl; a is an integer from 1to 2;

is selected from the group consisting of2-(2,3-dihydro-benzo[1,4]dioxinyl), 2-(benzo[1,3]dioxolyl),2-(3,4-dihydro-2H-benzo[1,4]dioxepinyl),2-(2,3-dihydro-benzo[1,4]dioxinyl),2-(6-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(6-fluoro-2,3-dihydro-benzo[1,4]dioxinyl), 2-(chromanyl),2-(5-fluoro-2,3-dihydro-benzo[1,4]dioxinyl),2-(7-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(6-chloro-benzo[1,3]dioxolyl),2-(7-nitro-2,3-dihydro-benzo[1,4]dioxinyl),2-(7-methyl-2,3-dihydro-benzo[1,4]dioxinyl),2-(5-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(6-bromo-2,3-dihydro-benzo[1,4]dioxinyl),2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(8-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(2,3-dihydro-naphtho[2,3-b][1,4]dioxinyl) and2-(4-methyl-benzo[1,3]dioxolyl); provided that when

is 2-(3,4-dihydro-2H-benzo[1,4]dioxepinyl), then a is 1; or apharmaceutically acceptable salt thereof.
 5. The method as in claim 4,wherein R¹ and R² are each independently selected from the groupconsisting of hydrogen and methyl; R⁴ is selected from the groupconsisting of hydrogen and methyl; a is an integer from 1 to 2;

is selected from the group consisting of 2-(benzo[1,3]dioxolyl),2-(2,3-dihydro-benzo[1,4]dioxinyl), 2-(2,3-dihydro-benzo[1,4]dioxinyl),2-(6-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(7-chloro-2,3-dihydro-benzo[1,4]dioxinyl),2-(7-methyl-2,3-dihydro-benzo[1,4]dioxinyl),2-(6-bromo-2,3-dihydro-benzo[1,4]dioxinyl) and2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxinyl); or a pharmaceuticallyacceptable salt thereof.
 6. The method of claim 1, wherein the compoundof formula (I) is selected from the group consisting of(2S)-(−)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide;and pharmaceutically acceptable salts thereof.
 7. A method of treatingobesity comprising administering to a subject in need thereof atherapeutically effective amount of a compound selected from the groupconsisting(2S)-(−)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide;and pharmaceutically acceptable salts thereof.
 8. A method of promotingweight loss comprising administering to a subject in need thereof atherapeutically effective amount of a compound selected from the groupconsisting(2S)-(−)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide;and pharmaceutically acceptable salts thereof.
 9. A method ofsuppressing appetite comprising administering to a subject in needthereof a therapeutically effective amount of a compound selected fromthe group consisting(2S)-(−)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide;and pharmaceutically acceptable salts thereof.
 10. A method for treatingobesity, promoting weight loss or suppressing appetite comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of formula (II)

or a pharmaceutically acceptable salt thereof.